Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008, Pamplona, Spain.
Curr Cancer Drug Targets. 2011 May;11(4):496-523. doi: 10.2174/156800911795538093.
Kinases are enzymes that are involved in a wide-range of cellular targets such as cell proliferation, metabolism, survival and apoptosis. Aberrations in the activity of the kinases have been linked to many human diseases such as diabetes, inflammation and cancer. The discovery of more than 518 kinases encoded by the human genome has spurred the development of rapid screening techniques for potential drugs against these enzymes and these have been identified as interesting targets for medicinal chemistry programs, especially in cancer therapy. On the other hand, sulfur and selenium have been increasingly recognized as essential elements in biology and medicine. Converging data from epidemiological and clinical studies have highlighted these elements as effective chemopreventive agents, particularly against various types of cancer (prostate, lung, breast, leukemia, colon, skin, lymphome, thyroid, pancreas, liver). These elements act through a wide range of potential mechanisms where one identified signal pathway event is kinase modulation, which is common for the two elements and emerges as a valid target. The kinases modulated by sulfur and selenium derivatives include MAP, ERK, JNK, Akt, Cdc2, Cyclin B1 and Cdc25c amongst others. Although both of the elements in question are in the same group in the periodic table and have similar biochemistries, there are relevant differences related to redox potentials, stabilities, oxidation states and anticancer activity. Literature data suggest that the replacement of sulfur by selenium in established cancer chemopreventive agents results in more effective chemopreventive analogs. In view of the multi-target kinase mechanisms in preventing cellular transformation, as well as the differences and similarities between them, in this review we focus on the development of new structures that contain selenium and/or sulfur and discuss our understanding of the regulation of antitumoral effects with emphasis on kinase modulation activity and its implications in cancer.
激酶是一种参与广泛细胞靶点的酶，如细胞增殖、代谢、存活和凋亡。激酶活性的异常与许多人类疾病有关，如糖尿病、炎症和癌症。人类基因组编码的超过 518 种激酶的发现，刺激了针对这些酶的潜在药物的快速筛选技术的发展，这些酶已被确定为药物化学项目的有趣靶点，特别是在癌症治疗方面。另一方面，硫和硒已越来越被认为是生物学和医学中的必需元素。来自流行病学和临床研究的综合数据强调了这些元素作为有效的化学预防剂的作用，特别是针对各种类型的癌症（前列腺癌、肺癌、乳腺癌、白血病、结肠癌、皮肤癌、淋巴瘤、甲状腺癌、胰腺癌、肝癌）。这些元素通过广泛的潜在机制发挥作用，其中一个确定的信号通路事件是激酶调节，这两种元素都很常见，并成为一个有效的靶点。硫和硒衍生物调节的激酶包括 MAP、ERK、JNK、Akt、Cdc2、Cyclin B1 和 Cdc25c 等。尽管这两种元素在元素周期表中属于同一族，具有相似的生物化学性质，但在氧化还原电位、稳定性、氧化态和抗癌活性方面存在相关差异。文献数据表明，在已确立的癌症化学预防剂中用硒替代硫会产生更有效的化学预防类似物。鉴于预防细胞转化的多靶点激酶机制，以及它们之间的差异和相似性，在这篇综述中，我们专注于开发含有硒和/或硫的新结构，并讨论我们对调节抗肿瘤作用的理解，重点是激酶调节活性及其对癌症的影响。
